Experiments in this competing renewal combine the powerful genetic tools of the model plant Arabidopsis with cell biological and biochemical approaches to examine a major signaling pathway that controls innate immunity and programmed cell death (PCD). The control of plant defenses has many parallels with human innate immunity. Furthermore, PCD has similar features and regulation in plants and humans. Our long term goal is to understand the molecular basis of PCD regulation and execution. This is essential for developing strategies to manipulate PCD to prevent or cure diseases involving excess or insufficient PCD induction in both plants and humans. What is learned from studying plant immunity and PCDwill be a paradigm for understanding similar events in humans. Experiments described herein build on previouswork on two Arabidopsis genes, ACD6 and ACD2. ACD6 is a novel integral plasma membrane protein with an N- terminal ankyrin repeat domain that controls defense and PCD in plants. Ankyrin repeats are involved in protein-protein interactions in plants, humans and many other organisms. ACD6 is important for both local and systemic signaling during infection. ACD2 is a novel protein that controls the activation and extent of PCD during infection by controlling the levels or reactivity of an endogenous PCD-inducingmolecule that is either a porphyrin or a porphyrin-like molecule. Thus, infection activates ACD6 to regulate defenses and PCD and ACD2 modulates the timing and extent of PCD to prevent excess tissue damage. The proposed research aims to: (i) determine the mechanism of action of ACD6 in activating PCD and disease resistance using molecular genetic and biochemical approaches; (2) determine the mechanism of action of ACD2 by combining molecular genetic, biochemical and physiological experiments; and (3) discern the properties and signaling requirements of cells that die due to porphyrin treatment (a surrogate for infection) using cell biological approaches. Porphyrins are important in anti-tumor therapies being developed. Therefore, it is important to know as much as possible about the effects that porphyrins have on cells. Dis-regulation of porphyrins in human (a condition called porphyria) causes severe disease to humans. ACD2 may provide a way to help people with this disease, since it likely has the potential to detoxify porphyrins. A number of human diseases are also caused by the malfunction of ankyrin-containing proteins. This work will generate important information about the whole class of ankyrin proteins that can be applied to understanding and possibly interrupting some human diseases. These studies will unravel common processes in plants and humans that can be manipulated to treat diseases caused by too much or too little cell damage. Because experimental progress using a plant model is rapid, the results obtained and quickly be related to human biology and disease.